Medication, reducing desire for alcohol, pharmaceutical composition and methods of its obtaining, medication and treatment method

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

 

The invention relates to active substance for the treatment of alcohol dependence, pharmaceutical compositions, medicinal product and method for the treatment of alcohol dependence from the use of products containing ethyl alcohol.

The majority of the population abusing products that contain ethyl alcohol, in the period of abstinence from the use of these products is experiencing a formidable attraction ("rod") for alcohol. The consequence of this alcohol dependence are recurrent episodes of abuse of products containing ethyl alcohol.

To date, proposed many treatments for alcohol dependence, the most famous of which include, for example, Naltrexone, Acamprosate, and gamma-sodium Oxybutyrate (SHB).

Naltrexone belonging to the group of antagonists of opioid receptors, which when used in combination with alcohol can reduce alcohol dependence, resulting in the decrease in the amount of alcohol consumed [U.S. Pat. EN 2090190]. It is known that the contraindications that restrict the use of Naltrexone, is the insufficiency of the liver [Krystal J.H., J.A. Cramer, Krol W.F., Kirk, G.F., R.A. Rosenheck; Veterans Affairs Naltrexone Cooperative Study 425 Group. Naltrexone in the treatment of alcohol dependence. N. Engl. J. Med. 2001, 345(24):1734-9].

Acamprosate also weakens alcohol dependence, resulting in a moderate decrease in the number used in further alcohol [Moncrieff J., Drummond D.C. New drug treatments for alcohol problems: a critical appraisal. Addiction. 1997, vol. 92, pp.939-47; discussion on str-64]. However, the contraindications that restrict the use of Acamprosate, refers to the liver [S.H. Williams Medications for treating alcohol dependence. Am. Fam. Physician. 2005, 72(9):1775-80]

Known drug containing as an active component of gamma-Hydroxybutyric acid or its salts, which when applied in the period of sobriety able to reduce alcohol dependence, resulting in further reduction in the number of relapses of alcoholism [F. Nava, Premi s, Manzato E., Campagnola W., Lucchini, A., Gessa G.L. Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam. Am. J. Drag Alcohol Abuse. 2007, 33: 379-392; 2007]. It is also known that the application of the gamma-Hydroxybutyric acid or its salts can cause symptoms of addiction [H.R. Sumnall, Woolfall K., Edwards, S., J.C. Cole, Beynon C.M. Use, function, and subjective experiences of gamma-hydroxybutyrate (GHB). Drag Alcohol Depend. 2008, 92(1-3):286-90], which complicates its safe use in patients with alcoholism. In this regard, gamma-hydroxybutyric acid or its salts are used mainly in pre-clinical studies as Comparators.

The search for effective and safe means the treatment of alcoholism remains a topical problem of modern medicine. Known medications for treating alcohol dependence, which are currently undergoing clinical studies. For example, in 2006, came to market Varenicline tartrate [EP 1078637, EP 1159970, EP 1177798], in phase III clinical trials is Neramexane hydrochloride [US 2006002999, US 6071966], in the stage of preclinical studies are drugs MTIP [WO 2006102194] and CVT-10216 [WO 2008014497].

Known substituted 1H-benzimidazole of General formula 1 and their pharmaceutically acceptable salts and/or hydrates with different types of pharmacological activity

where W represents a sulfur atom or a group S=O; R1represents one or more substituents selected from hydrogen, halogen, C1-C4of alkyl, C1-C4alkyloxy, optionally substituted azaheterocycle;

R2represents hydrogen or optionally substituted C1-C4alkyl;

R3and R4independently from each other are not necessarily identical substituents selected from hydrogen or optionally substituted C1-C4of alkyl;

R5is an alkyl substituent selected the C hydrogen, optionally substituted C1-C7the alkyl, optionally substituted aryl, optionally substituted heterocyclyl,1-C4alkoxycarbonyl, optionally substituted aminocarbonyl.

Table 1 presents the known substituted 1H-benzimidazole of General formula 1 and their pharmacological activity.

Table 1
Pharmacologically active substituted 1H-benzimidazole of General formula 1
No. of connectionsFormulaPurposePatent
1.1nootrop, improve memory, protect the liverSU 1251374;
EN 2188012
1.2the anxiolytic, treatment of anxiety and cognitive disordersEP 0788795

1.3treatment of stomach ulcers and dvenadcatiperstnoj the ulcer US 5106863
1.4treatment of gastric ulcer and duodenal ulcerUS 5106863
1.5treatment of gastric ulcer and duodenal ulcerUS 5106863
1.6treatment of lipoprotein disordersWO 2005003119
1.7treatment of gastric ulcer and duodenal ulcerEP 0457331
1.8treatment of gastric ulcer and duodenal ulcerEP 0370436
1.9treatment of gastric ulcer and duodenal ulcerEP 0452076

1.10 treatment of gastric ulcer and duodenal ulcerJP 1991014566
1.11treatment of atherosclerosisWO 2001000588
1.12treatment of atherosclerosisWO 2001000588
1.13the analgesic treatment of painWO 2002040019
1.14the analgesic treatment of painWO 2002040019
1.15treatment of obesity and sleep disordersWO 2007126934

1.16the treatment of asthma and allergiesEP 0287971 (B1)
1.17 the anxiolytic, analgesic, treatment of anxiety and cognitive disorders, treatment of painWO 2004014881; WO 20050773465

Known and other, commercially available ChemDiv Inc. [www.chemdiv.com] substituted 1H-benzimidazole of General formula 1, some of them are presented in table 2.

Table 2
Commercially available substituted 1H-benzimidazole of General formula 1
No. of connectionsFormulaNo. of connectionsFormula
1.181.36
1.191.37
1.201.38

1.211.39
1.221.40
1.231.41
1.241.42
1.251.43
1.261.44

1.271.45
1.28 1.46
1.291.47
1.301.48
1.311.49
1.321.50

1.331.51
1.341.52
1.351.53
1.54

Known drug - hydrobromide 2-ethylsulfanyl-1H-benzimidazole (Bemythyl) 1.1, which has neuroprotective and antiasteniceski action [SU 1251374], and can also improve the process of liver regeneration [EN 2188012], including to exert a protective effect on the liver in patients with alcoholism [acavity S.V., Ivanov O.V., Shabanov P.D. Hepatoprotective effect bemythyl in patients with chronic alcoholic liver disease. Narcology, 2002, No. 3, p.19-23].

Known drug - dihydrochloride of 2-[2-(morpholine-4-yl)-ethylsulfanyl]-5-acyloxy-1H-benzoimidazole (Afobazol) 1.2 for the treatment of anxiety disorders [EP 0788795].

However, for Bemythyl 1.1, Afobazole 1.2 and others are presented in tables 1 and 2 famous substituted 1H-benzimidazole of General formula 1 for the treatment of alcohol dependence is not known.

Below are definitions of terms used in the description of this invention.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more "froze the Fort worth round Robin" system.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, ethyl, propyl, cyclopropylmethyl, cyclopentylmethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-Penta is l, 3 pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Alkylamino" means CnH2n+1NH - or (CnH2n+1)(CnH2n+l)N - group in which alkyl is defined in this section. The preferred alkylaminocarbonyl are methylamino, ethylamino, n-propylamino, out-propylamino and n-butylamine.

"Alkyloxy" means CnH2n+1O - group in which alkyl is defined in this section. The preferred alkyloxyaryl are metiloksi, ethyloxy, n-propyloxy, out-propyloxy and n-Butylochka.

"Amino group" means RkaRk+1aN - group, substituted or unsubstituted "Deputy amino group" Rkaand Rk+1athe value which is defined in this section, for example, amino (Hsub> 2N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamine or phenethylamine.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preimushestvenno from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. "Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Deputy" means a chemical moiety which joins scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, glogan, nitro, qi is but carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkyloxyalkyl, aryloxyalkyl, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskikh, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylthio, aaltio, heterocyclic, heterocyclic, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylthiomethyl, alltoall, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskie, arylalkylamines, geterotsiklicheskikh, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino, RkaRk+1aN-, RkaN=, RkaRk+1aN-alkyl-, RkaRk+1aNC(=O)- or RkaRk+1aNSO2-, where Rkaand Rk+1arepresent independently from each other "Vice-amino group", which is defined in this section, for example hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroalkyl, or the substituent RkaRk+1aN-, in which Rkamo is et to be acyl or aroyl, and a value of Rk+1adefined above, or "Deputy cyclic system are RkaRk+1aNC(=O)- or RkaRk+1aNSO2-, in which Rkaand Rk+1atogether with the nitrogen atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl.

"Active ingredient" (drug substance or drug, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active substance in the pharmaceutical composition used for the production and manufacture of drugs (drug).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions, in the form of tablets, capsules, injections, ointments and other ready-made forms designed to restore, correct or modify physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"The pharmacy is practical composition" denotes a composition includes the compound of the formula I and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylenesorbitan and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved by using agents to slow absorbs the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal introduction of the active substance, one or in combination with another active ingredient, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, p is drainie, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of these salts is given in S.M. Berge et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.) Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most the desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The object of the present invention is an active substance for the treatment of alcohol dependence of humans and warm-blooded animals, which represents a substituted 1H-benzimidazole of General formula 1 and their pharmaceutically acceptable salts and/or hydrates.

Prefer the lnoe active substance is a hydrobromide 2-ethylsulfanyl-1H-benzimidazole of formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)ethylsulfanyl]-5-acyloxy-1H-benzimidazole of formula 1.2.

The subject of this invention is also a pharmaceutical composition for the treatment of alcohol dependence of humans and warm-blooded animals containing a pharmaceutically effective amount of the active substance, representing at least one substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate.

Preferred pharmaceutical composition contains as active ingredient the hydrobromide of 2-ethylsulfanyl-1H-benzimidazole and formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)ethylsulfanyl]-5-acyloxy-1H-benzimidazole of formula 1.2.

The subject of this invention is also a pharmaceutical composition for the treatment of alcohol dependence of humans and warm-blooded animals containing a pharmaceutically effective amount of the active substance, representing at least one substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate and antidepressant.

In this case, there is a synergistic action of substituted 1H-benzimidazole of General formula 1 and antidepressant expressed in more effective treatment of alcohol dependence at lower dosages of the substances.

As antidepressants can be used, for example, hydrochloride, 5-methyl-2,3,7,8,9,10-hexahydro-1H-feast of the Ino[3,2,1-jk]carbazole formula 2.1 (Pirazidol) [GB 1340528; EN 0276060; WO 206048242], hydrochloride 5-cyclohexyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.2 (Tetrindol) [Glushkov, R.G.; Mashkovsky, M.D.; Andrejeva, N.I.Tetrindole. Drugs Fut, 1997, 22(12), 1333; Mashkovsky PPM, Glushkov RG, Swedes V., Andreeva N, Golovin S.M. Exp. The wedge. Pharmacol. 1993, 56(2), 3-6], the hydrochloride of N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane-1-amine 2.3 (Prozac) [EP 0830864; US 4314081; US 6927223; WO 1992018005; WO 2007064586], 2-(diphenylmethylene)ndimethylacetamide 2.4 (Modafinil) [EP 0462004; EP 0547952; EP 0594507; US 2007065517; US 4177290; WO 1995000132; WO 2006030278; WO 2006032146], hydrochloride methyl-(2,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)amine 2.5 (Mecamylamine) [US 2831027; US 6034079; WO 1999015492; WO 2007075720], 7-{4-[4-(2,3-dichlorophenyl)piperazine-1-yl]butoxy}-3,4-dihydro-1H-quinoline-2-he 2.6 (Aripiprazole) [EP 0367141; US 2005245541; WO 2002060423; WO 2007118923], fumarate, 2-[2-(4-dibenzo[b,f][1,4]diazepin-11-reparacin-1-yl)ethoxy]ethanol 2.7 (Quetiapine fumarate) [EP 0240228; JP 2005060286; US 6599897; WO 1997045124; WO 2007058593], hydrochloride 1-(3-dimethylaminopropyl)-1-(4-forfinal)-1,3-dihydroisobenzofuran-5-carbonitrile 2.8 (Nitalapram) [SA 2163840; EP 0474580; US 2002061925; WO 2000012044; WO 2006103550] and others.

More preferred pharmaceutical composition contains as antidepress the NTA hydrochloride 5-methyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.1, or hydrochloride 5-cyclohexyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.2, or the hydrochloride of N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane-1-amine of formula 2.3.

The pharmaceutical composition may include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with the active ingredient of the present invention may include other active ingredients provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers, for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms (such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, represent the FDS is th media used in pharmaceutical industry to obtain common forms, including oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The subject of this invention is also a method of obtaining a new pharmaceutical composition by mixing a pharmaceutically effective amount of the active substance, representing at least one of substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate with an inert filler and/or diluent.

The subject of this invention is also a method of obtaining a new pharmaceutical composition by mixing with an inert filler and/or solvent pharmaceutically effective amount of an antidepressant and an active agent, representing at least one of substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate.

The subject of this invention are the medicinal product in the form of the of Ableton, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment of alcohol dependence, including a pharmaceutically effective amount of the active substance, representing at least one of substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition of the present invention.

The subject of this invention are the medicinal product in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment of alcohol dependence, including a pharmaceutically effective amount of an antidepressant and an active agent, representing at least one of substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition of the present invention.

Preferred is a drug, comprising as active ingredient the hydrobromide of 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2, and as an antidepressant hydrochloride 5-methyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.1, or the hydrochloride of 5-cyclohexyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]ka is basola formula 2.2 or hydrochloride of N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane-1-amine 2.3.

More preferred is a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment of alcohol dependence, which represents a pharmaceutically effective combination of two drugs: antidepressant medicines, including a pharmaceutically effective amount of the active substance, representing at least one of substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate, or hydrobromide 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2 or a pharmaceutical composition of the present invention.

In accordance with this invention a method of treating alcohol dependence people is the introduction of pharmaceutically effective quantity of active compound or pharmaceutical composition or a pharmaceutically effective quantity of a new drug.

In accordance with this invention the active substance, pharmaceutical compositions and drug use in treatment of alcohol dependence people.

Drugs can be administered orally or parenterally (EmOC is emer, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the active substance, pharmaceutical composition or drug, including a pharmaceutically effective amount of the active substance, representing at least one substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate, patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. So in the time of preparation of the pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The examples below illustrate the invention.

The invention is illustrated by the diagram shown in the drawing, showing the influence of a 4-day deprivation of access to 10% ethanol solution on a voluntary consumption by male mice of SHK. The abscissa axis is consumed amount of alcohol in terms of pure alcohol*, - alcohol-deprivation effect (RANS), LS-Fisher test (ANOVA).

The criterion for alcohol dependence is an increase in the consumption of a solution of the alcohol resulting from transient deprivation of alcohol, which is a model of loss of control during a binge [may A.I., Salimov P.M. HOWTO on the study of drugs to treat alcoholism. Manual on experimental (preclinical) study of new pharmacological substances, ed Gabriel RU, Moscow: Medicine, 2005, s-356].

To overcome the possible initial taste of rejection of a solution of alcohol during the first 6 days of the experiment, male mice SHK has not received water, and had access only to the solution of increasing alcohol concentrations (3% in day 1; 2, 6% in day 3 and 4, and 10% on day 5 and 6) [McKinzie et al., Alcohol Clin Exp Res. 1998, 22(7): 1584-90]. They had free access to food. Over the next 2 months, the mice had free access to clean water, food, a 10% solution of alcohol.

To assess alcohol motivation was to calculate the degree of increase in voluntary consumption of 10% solution of alcohol during the 90-minute test after 4 days of deprivation of alcohol compared with the same test, performed to a 4-day deprivation of alcohol (alcohol-deprivation effect, the TE). Index RANS was calculated as the ratio of alcohol consumption after its cancellation (counting the grams of pure alcohol per kilogram of body weight) to the total consumption before and after the abolition of access to alcohol. If the index RANS has a value greater than or less than 0.5, it means respectively the presence or absence of alcohol dependence.

After the 2-month period of free access mice to water and alcohol have performed the above-described evaluation of RANS and further experiments were selected mice, in which the index RANS was greater than 0.5. These mice were divided into groups of 9-12 individuals, which did not differ from each other by RANS.

As a drug comparison in experiments with male mice of SHK used gamma-sodium Oxybutyrate.

Example 1. This example shows the reaction of the mice, which in the period of deprivation of alcohol with non-traumatic probe inside the esophagus were injected with sterile water. As can be seen from the drawing, the dose of alcohol consumed by the mice during the first 30 minutes of the test after an alcohol deprivation, 169% more than the deprivation of alcohol. In accordance with the existing view that shows the data of mice alcoholic motivation, which strengthened after a period of forced sobriety [may A.I., Salimov P.M. HOWTO on the study of drugs DL the treatment of alcoholism. Manual on experimental (preclinical) study of new pharmacological substances, ed Gabriel RU, Moscow: Medicine, 2005, s-356].

Example 2. This example shows voluntary alcohol consumption and alcohol-deprivation effect (table 3) in mice with the generated alcohol dependence, which in the period of deprivation of alcohol with non-traumatic probe in the esophagus was given a placebo (sterile water), gamma-sodium Oxybutyrate, substituted 1H-benzimidazole of General formula 1 or its pharmaceutically acceptable salt and/or hydrate, such as bemythyl 1.1 (0.5 to 20 mg/kg), and antidepressant, for example tetrindol (2 or 10 mg/kg). A separate group of animals in the same way introduced connection 1.54 General formula 1 in a dose of 5 mg/kg Introduction was made orally 1 time a day for 4 days in a row.

Table 3
Voluntary alcohol consumption and alcohol-deprivation effect in mice with the generated alcohol dependence
MedicationDose, mg/kgAlcohol consumption, g/kgRANS
to after
deprivation
Placebo1,4±0,654.26 deaths±0,950,69±0,06
SHB1502,36±0,751.49±1,100,45±0,07
1.1 Bemythyl0,51,96±0,754,36±1,100,65±0,07
1.13,03,49±0,752,60±1,100,46±0,07
1.110,02,79±0,751,59±1,100,39±0,07
1.120,02,56±0,751,55±1,100,31±0,07
1.545,01,26±0,331,40±0,350,49±0,06
2.2 Tetrindol2,0 2,61±0,793,42±1,160,58±0,08
2.210,02,61±0,75of 5.05±1,100,61±0,07
1.1+2.20,5+2,01,50±0,710.77±1,040,35±0,07
1.54+2.20,5+2,01,14±0,300,83±1,020,42±0,07

The results presented in table 3 show that the alcohol-deprivation effect in terms of increased alcohol consumption after 4 days of deprivation, is observed only in the groups of mice that were given a placebo, Bemythyl 1.1 at a dose of 0.5 mg/kg and Tetrindol 2.2 at doses of 2 and 10 mg/kg In other groups, which were introduced Bemythyl 1.1 (3-20 mg/kg), the active ingredient 1.54 (5.0 mg/kg) of General formula 1 or Bemythyl 1.1 (0.5 mg/kg) in combination with Tetrindola 2.2 (2 mg/kg) or active substance 1.54 (0.5 mg/kg) of General formula 1 in combination with Tetrindola 2.2 (2 mg/kg), was not observed postdeprivation increase in alcohol consumption. These differences are most clearly visible on the index value RANS (table 3).

Thus, as can be seen from table 3, the product comparison is possible gamma-sodium Oxybutyrate (SHB) causes a marked reduction in alcohol-deprivation effect, that testifies to the weakening of alcohol dependence. A similar effect has substituted 1H-benzimidazole of General formula 1 or their pharmaceutically acceptable salts, such as Bemythyl 1.1 in a dose-dependent manner, the effect of which appears in the dose of 3 mg/kg and increases in the dose of 20 mg/kg of Antidepressants, for example Tetrindol 2.2, when a stand-alone application in doses of 2-10 mg/kg does not have the ability to influence RANS. However, if the maximum is not valid (subeffective) dose (0.5 mg/kg) Bemythyl 1.1 (0.5 mg/kg) together with Tetrindola 2.2 showed marked synergistic action and reduction of RANS to the value of 0.35±0.07 (table 3). Active substance 1.54 General formula 1 in a stand-alone application or in combination with Tetrindola 2.2 also reduced RANS. These results indicate that substituted 1H-benzimidazole of General formula 1 or pharmaceutically acceptable salt (for example, active substance 1.54 and Bemythyl 1.1) in doses of 3 to 20 mg/kg or substituted 1H-benzimidazole of General formula 1 or pharmaceutically acceptable salt subeffective dose in combination with antidepressants (for example, Tetrindola 2.2) are effective in reducing alcohol dependence.

The data presented demonstrate the ability of the active substance, pharmaceutical compositions and medicaments that include the dei is adequate substance, loosen objectively recorded symptoms of alcohol dependence - increase the dose of alcohol consumed after a period of sobriety. In addition, in comparison with the known drug Acamprosate or Naltrexone the claimed active ingredient, the pharmaceutical composition and the drug, including this active substance, does not have adverse effects on liver function.

1. Means for reducing the craving for alcohol that represents a substituted 1H-benzimidazole of General formula 1 or their pharmaceutically acceptable salts and/or hydrates,

where W represents a sulfur atom or a group S=O;
R1represents one or more substituents selected from hydrogen, halogen, C1-C4of alkyl, C1-C4alkyloxy, optionally substituted 5-6-membered azaheterocycles with 1-2 nitrogen atoms and/or oxygen in the loop;
R2represents a hydrogen atom or optionally substituted C1-C4alkyl;
R3and R4independently from each other are not necessarily identical substituents selected from hydrogen, optionally substituted C1-C4of alkyl, C3-C6cycloalkyl;
R5is an alkyl substituent selected from hydrogen or the optional is tion substituted C 1-C7of alkyl, C1-C7alkenyl,1-C4the quinil, optionally substituted phenyl, optionally substituted 5-6-membered heterocyclyl with 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, possibly condensed with a benzene ring; With1-C4-alkoxycarbonyl, optionally substituted aminocarbonyl, or group of CR3R4R5together mean a groupwhere Alk means1-C4alkyl.

2. The tool according to claim 1, which represents the hydrobromide of 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)-ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2.

3. Pharmaceutical composition for reducing the craving for alcohol that contains a tool of General formula 1 according to claim 1 as an active ingredient in an effective amount.

4. The pharmaceutical composition according to claim 3, containing as the active component of the hydrobromide of 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)-ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2 according to claim 2 in an effective amount.

5. Pharmaceutical composition for reducing the craving for alcohol, containing the active ingredient of General formula 1, or 1.1, or 1.2, and antidepressant medication in the effect is positive number.

6. The pharmaceutical composition according to claim 5, comprising as antidepressant hydrochloride 5-methyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.1 or hydrochloride 5-cyclohexyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.2 or hydrochloride of N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane-1-amine 2.3

7. A method of obtaining a pharmaceutical composition according to any one of p or 4 mixing tools General formula 1, or 1.1, or 1.2 according to claim 1 or 2 with an inert filler and/or diluent.

8. A method of obtaining a pharmaceutical composition according to any one of subparagraph 5 or 6 mixing tools General formula 1, or 1.1, or 1.2 according to claim 1 or 2, and antidepressant with an inert filler and/or diluent.

9. A drug that reduces the craving for alcohol in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the treatment of alcohol dependence, including the tool according to claim 1 or 2, or a pharmaceutical composition according to any one of p-6 in an effective amount.

10. The drug according to claim 9, comprising as an active ingredient the hydrobromide of 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)-ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2, or in pharmaceutical preparations is practical composition according to claim 4 in an effective amount.

11. The drug according to claim 9, comprising as an active ingredient the hydrobromide of 2-ethylsulfanyl-1H-benzoimidazole formula 1.1 or a dihydrochloride of 2-[2-(morpholine-4-yl)-ethylsulfanyl]-5-acyloxy-1H-benzoimidazole formula 1.2 and as an antidepressant hydrochloride 5-methyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.1, or the hydrochloride of 5-cyclohexyl-2,3,7,8,9,10-hexahydro-1H-pyrazino[3,2,1-jk]carbazole formula 2.2, or the hydrochloride of N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propane-1-amine of formula 2.3, or a pharmaceutical composition according to claim 6.

12. The way to reduce the desire for alcohol by the introduction of a pharmaceutically effective amount according to claim 1 or 2, or a pharmaceutical composition according to any one of p-6, or drugs on any of PP-11.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrolotriazines of formula (I) , where R1 is selected from a group which includes phenyl, naphthyl, benzyl and heteroaryl, which denotes a mono- or bicyclic radical containing 5-10 ring atoms and up to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulphur, at least one ring of which is aromatic, where, if necessary, phenyl and heteroaryl may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of -(C1-C4)alkyl, where -(C1-C4)alkyl can be substituted with 0, 1, 2 or 3 halogens, 0 or 1 pyrrolidine, -(C1-C3)alkoxy group, where, if necessary, the (C1-C3)alkoxy group may be substituted with a (C1-C3)alkylamino group, halogen, trifluoromethyl, trifluoromethoxy group, phenyl, if necessary substituted with 1 or 2 halogens, - , where X denotes O, nitro group, - (C1-C3)alkylthio group, trifluoromethylthio group, - (C1-C3)alkylcarbonyl, - (C1-C6)alkoxycarbonyl, and a phenoxy group, and where the benzyl can be substituted with 0, 1, 2 or 3 groups selected from a group which includes halogen; R2 is selected from a group consisting of hydrogen, halogen; R3 is selected from a group consisting of carboxyl, - (C1-C6)alkylcarbonyl, - (C3-C6)cycloalkylcarbonyl, - (C1-C6)alkoxycarbonyl, if necessary substituted with 0, 1, 2 or 3 groups selected from a group which includes amino group and (C1-C6)alkoxycarbonyl; aminocarbonyl, -(C1-C6)alkylaminocarbonyl, where (C1-C6)alkylaminocarbonyl which, if necessary, can be substituted with 0, 1, 2 or 3 substitutes independently selected from a group consisting of (C3-C6)cycloalkyl, halogen, amino group, (C1-C6)alkylamino group, hydroxy group, (C1-C6)alkoxy group, (C1-C6))alkoxycarbonyl, (C1-C6)alkylthio group, (C1-C6)alkoxycarbonylamino group,and where, if necessary, (C1-C6)alkylaminocarbonyl may be substituted with 0 or 1 heterocyclyl, which denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, where, if necessary, the hetecyclyl may be substituted with 0 or 1 (C1-C6)alkyl, heterocyclylcarbonyl, if necessary substituted with 0 or 1 (C1-C6)alkylamino group, cycloalkyl or (C1-C6)alkyl,where, if necessary, (C1-C6)alkyl may be substituted with 0 or 1 (C1-C6)alkylamino group, and where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, -(C1-C6)alkyl if necessary substituted with 0, 1 or 2 substitutes independently selected from a group consisting of a) hydroxyl, b) (C1-C6)alkylamino group, where (C1-C6)alkylamino group may be substituted with 0, 1 or 3 substitutes independently selected from a group consisting of halogen, alkylamino group, methoxy group, methylthio group and methylsulphonyl, c) phenylamino group, where the phenylamino group may be substituted with 0, 1 or 2 substitutes independently selected from a group consisting of (C1-C6)alkoxy group and trifluoromethyl, d) heterocyclyl, where heterocyclyl denotes a monocyclic, non-aromatic radical containing 5-8 ring atoms and up to 2 heteroatoms selected from nitrogen and oxygen, and where the heterocyclyl may be substituted with 0 or 1 (C1-C6)alkyl, where (C1-C6)alkyl may be substituted with 0 or 1 methoxy groups or pyridyls, e) imidazolyl, f) pyridylamino group, g) (C1-C3)alkoxy group, if necessary substituted with fluorine or piperidine,where, if necessary, the piperidine may be substituted with 0 or 1 (C1-C6)alkyl, h) (C1-C3)alkoxy(C2-C3)alkoxy group, and i) (C1-C6)alkoxycarbonyl, j) (C3-C6)cycloalkyl, k) cyano group, - (C3-C6)cycloalkylaminocarbonyl, cyano group, heteroaryl, where heteroaryl denotes a monocyclic radical containing 5-6 ring atoms and up to 3 heteroatoms selected from a group consisting of nitrogen and oxygen, the ring of which is aromatic, where the heteroaryl may be substituted with 0, 1 or 2 groups independently selected from a group consisting of q) (C1-C6)alkyl, where the (C1-C6)alkyl may be substituted with 0 or 1 morpholine or 0 or 1 hydroxy group, r) (C1-C6)alkoxycarbonyl, thiophene carbonyl, and R4 is selected from a group consisting of hydrogen; to a pharmaceutically acceptable salt thereof. The invention also pertains to methods of obtaining said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for preventing or treating hyper-proliferative disorders and diseases associated with angiogenesis.

5 cl, 313 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one, which exhibits characteristic peaks on an X-ray powder diffraction pattern expressed in two-theta degrees, selected from approximately 7.1, approximately 12.1 and approximately 16.1; or approximately 7.1, approximately 12.1 and approximately 17.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 12.1, approximately 16.1 and approximately 17.5; or approximately 12.1, approximately 16.1 and approximately 23.5; or approximately 16.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 17.5 and approximately 23.5; or approximately 7.1, approximately 12.1 and approximately 23.5; or approximately 7.1, approximately 16.1 and approximately 23.5, and to a pharmaceutical composition based on said compound, which can be used in medicine to prepare a medicinal agent which acts on the hepatitis C virus (HCV) in HCV-infected mammals.

EFFECT: improved properties of derivatives.

12 cl, 1 tbl, 3 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):

R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.

EFFECT: obtaining new biologically active compounds.

26 cl, 12 dwg, 4 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula: , where R1 - C1-C6alkyl, C1-C6alkoxy, halogen, CN, C(O)NH2 or OCH2CH2OCH3; R2-C1-C6alkyl, possibly substituted with halogen, a halogen, C1-C6alkoxy, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, where n equals 1 or 2; m equals 2 or 3; R6 -R7 -C1C6alkyl, and R8 -OCH2CH2OCH3; or R7 and R8 together with the nitrogen atom to which they are bonded form a 6-member heterocycle which additionally contains one oxygen atom or one nitrogen atom, which in the latter case is substituted with C1-C4alkyl; or R1 and R2 together form a 5-member heterocyclic ring system containing two oxygen atoms as heteroatoms; R3 - hydrogen or C1-C6alkyl; R4 - hydrogen, halogen or C1-C6alkoxy; or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds with kinase inhibiting properties, particularly CDK2, or angiogenesis inhibiting properties and can be used in treating malignant growths, particularly in mammary glands, large intestines, lungs and prostate glands.

60 cl, 7 tbl, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, where X is CH; R1 is phenyl or a 6-member heteroaryl which contains 1 or 2 nitrogen atoms as heteroatoms, independently and optionally substituted with up to five groups J; R2 and R3 each independently represents hydrogen, halogen, -V-R or -V-Ra; R5 is R; R is H or an optionally substituted C1-6aliphatic group, where the substitutes are selected from -OR0, phenyl, substituted R0, -N(R0)2; where each independent R0 is selected from hydrogen, halogen, C1-6aliphatic group; Ra is morpholine, V is a bond or Q; Q is -NR5-; each J group independently represents a halogen, -N(R5)2. The invention also relates to a pharmaceutical composition with protein kinase inhibiting properties, and to methods of inhibiting Aurora A protein kinase using the said compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which can be used in medicine to treat or alleviating a proliferative disorder, such as cancer, in a patient.

25 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to pyrido[1,2-a]benzimidazole derivatives of general formula I, where R=alkyl; R1=alkyl, aryl; R2=alkyl. The invention also relates to a method of producing formula I compounds.

EFFECT: novel to pyrido[1,2-a]benzimidazole derivatives with antibacterial activity are obtained.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention discloses pharmaceutical compositions based on telozolomide-8-carboxylate compounds of general formula I, as well as a method of preparing the said compositions. The disclosed composition has anti-tumour activity and can be especially useful during transdermal application.

EFFECT: obtaining compositions which, along with conventional pharmaceutical carriers, contain a component of acidic nature which gives the pharmaceutical composition high resistance to pH fluctuation.

16 cl, 2 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I in the form of salt where J means a C1-C2 alkylene; R1 means cyclopentane, cyclohexyl, phenyl or thiophenes; R2 means hydroxy; R3 means a cyclopentane, cyclohexyl, phenyl or thiophenes; with R1 and R3 are not identical, or -CR1R2R3 together form a group of the formula , where Ra means a chemical bond, and Rb means hydroxy; R4 means methyl; R5 means C1 alkyl substituted with -CO-NH-R6; R6 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur; or J means C1-C2 alkylene; R1 and R3 both mean phenyl; R2 means hydroxy; R4 means methyl, R5 means C1 alkyl substituted with -CO-NH-R9; and R9 means 5- or 6-membered heterocyclic group that contains in a cycle at least one heteroatom selected from nitrogen, oxygen and sulfur. The invention also refers to pharmaceutical composition, to application of compound according to any of clauses 1-3, as well as to method for obtaining a compound of formula I according to clause 1.

EFFECT: obtaining new biologically active compounds having antagonistic activity against muscarinic receptor M3.

7 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

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